Method of preparing a radioactive yttrium phosphate particle suspension

ABSTRACT

A method of preparing a radioactive yttrium salt particle suspension comprising multiple steps comprising: using a hydrothermal process wherein a solution of soluble yttrium salt, from the group of yttrium chloride, yttrium nitrate, yttrium sulfate, and yttrium bromide is combined with a solution of sodium phosphate having a stoichiometric excess of phosphate and a preferred pH when combined.

This application is a Section 371 Nationalization of Korenko et al PCTapplication no. PCT/US2020/035733, filed 2 Jun. 2020; and is acontinuation of Korenko et al U.S. patent application Ser. No.16/459,466 filed 1 Jul. 2019, both of which are hereby incorporated intothis application by reference

FIELD AND BACKGROUND OF THE INVENTION

A method of preparing a radioactive yttrium phosphate particlesuspension for the treatment of tumors including solid tumors.

Any patents and publications referred to herein are incorporated hereinby reference

SUMMARY OF THE INVENTION

The method claimed is the preparation of radioactive yttrium phosphateparticles of a size preferred for interstitial application in solidtumors.

BRIEF DESCRIPTION OF THE FIGURES

The foregoing and other features and advantages of the present inventionwill become more readily appreciated as the same become betterunderstood by reference to the following detailed description of thepreferred embodiment of the invention when taken in conjunction with theaccompanying drawings, wherein:

FIG. 1 illustrates particle size determined through the claimed processwith pH of 7.35 yielding particle median size of 0.2450 μm. And FIG. 2with pH 7.4 and median particle size of 0.1844 μm with particles in eachof FIG. 1 and FIG. 2 providing interstitial effectiveness for cell spaceapplication.

The foregoing descriptions of specific embodiments of the presentinvention have been presented for purposes of illustration anddescription. They are not intended to be exhaustive or to limit thepresent invention to the precise forms disclosed, and obviously manymodifications and variations are possible in light of the abovedescription and figures. The exemplary embodiment was chosen anddescribed in order to best explain the principles of the presentinvention and its practical application for purposes of enabling otherswho are skilled in the art and making of the product to best utilize thepresent invention and various embodiments with various modifications asare suited to the particular use contemplated.

DETAILED DESCRIPTION OF THE INVENTION

A method of preparing a radioactive yttrium salt particle suspensioncomprising multiple steps comprising: using a hydrothermal processwherein a solution of soluble yttrium salt from the group of yttriumchloride, yttrium nitrate, yttrium sulfate, and yttrium bromide iscombined with a solution of sodium phosphate having a stoichiometricexcess of phosphate and pH when combined in the range of 1.5 to 8 andpreferably pH in the range of 7 to 8.

Combining the solutions with continuous stirring and rapidly heating ina closed vessel to 150° C. and held for 1 to 10 hours to yield greaterthan 99.99% conversion of soluble yttrium to insoluble YPO₄ and toachieve the desired particle size distribution and;

Creating the desired particle size distribution of YPO₄ particlessuspended in buffered saline at neutral pH suitable for direct injectioninto human or animal tissue.

The radioactive particle suspension wherein the particle size is lessthan 2 μm.

The radioactive particle suspension comprised of at least 90 percent ofthe total particle volume consisting of particles in the range of 0.1μto 2 μm.

And further comprising: wherein the starting concentration of solubleyttrium in the combined solution is in the range of 0.5 to 3.0mole/liter and the stoichiometric excess of phosphate ranges from 10 to100%.

And further, comprising: the starting concentration of soluble yttriumin the combined solution is 0.08 moles/liter and the stoichiometricexcess of phosphate is 25%.

The method further comprising: the particle suspension formed bypreparing the particle precursor solution, mixing and heating to formthe YPO₄ particles by controlled precipitation followed bypost-processing the particles to achieve a suspension of YPO₄ particlesin phosphate buffered saline solution at neutral pH suitable forinjection into human or animal tissue.

The method further comprising: the particle suspension wherein the postprocessing consists of rinsing the particles 3 times with sterilephosphate buffered saline (PBS) solution and removing or adding PBS toachieve the final desired volume.

The method further comprising: the particle suspension wherein the postprocessing consists of adjusting the pH of the final solution withsodium hydroxide then removing excess solution or adding sterile PBS toachieve the final desired volume.

The method further comprising: the particle suspension wherein theyttrium phosphate particles are radioactive to serve as distributedsources of therapeutic radiation for treating cancerous tumors and otherdiseases and: making the particles radioactive by adding a small mass ofsoluble radioactive isotope to the particle precursor solution thatbecomes homogeneously incorporated into the insoluble yttrium phosphateparticle matrix.

The method further comprising; the yttrium phosphate particle suspensionwherein the particle concentration is in the range of 40 mg/mil to 125mg/ml to facilitate imaging by x-ray computed tomography after beingcombined in a ratio of 1 to 4 by volume with biocompatible hydrogel orother suitable liquid carrier solution for injection into human oranimal tissue.

Example I

One exemplary process for practicing the method of the present inventionis shown below:

Step 1—preparing reagents by:

Step 1.1—weighing out a non-radioactive (i.e., Y-89) yttrium salt fromthe group of yttrium chloride, yttrium nitrate, yttrium sulfate, andyttrium bromide and transferring quantitatively to a volumetric flask;adding deionized water; agitating to mix completely; and

Step 1.2—drawing up the ⁸⁹Y⁺³ solution from the volumetric flask into asyringe and pushing the solution through a filter and collecting thesolution in a sterile container; and

Step 1.3—preparing and filtering 0.15 M Na₂HPO4 and 0.05 M HCl reagents;storing the reagents at room temperature; and

Step 2—preparing a radioactive ⁹⁰YCl₃ solution by:

Adding to a source vial containing ⁹⁰YCl₃ sufficient volume of 0.05 MHCl, to achieve recovery of the desired quantity of radioactive materialfrom the source vial; and

Step 3—performing a radioactive (⁸⁹Y+⁹⁰Y) PO₄ synthesis procedure by:

Step 3.1—adding H₂O to the microwave reaction vial with a sterilemagnetic stir bar; and placing the reaction vessel on a stir plate; andwith continuous stirring;

Step 3.2—adding 0.15 M Na₂HPO₄; and

Step 3.3—adding ⁸⁹Y⁺³ solution; and

Step 3.4—adding ⁹⁰Y in 0.05 M HCl from a source vial; and

Step 3.5 recording the final pH; and

Step 3.6—transferring the vial to a microwave reactor; and

Step 3.7—setting the reaction temperature to a temperature in the rangeof 110° C. to 160° C. and reaction time to between one hour and 20 hoursand starting the reactor;

Step 4—performing final steps comprising:

Step 4.1—placing the microwave vial with the particles in a centrifuge,subjecting the particles to centrifugation; and

Step 4.2—removing the supernatant liquid and replacing it with sterilephosphate buffered saline, and repeating Steps 4.1 and 4.2 twoadditional times, and

Step 4.3—removing excess supernatant liquid from the vial; and

Step 4.4—properly labeling the vial.

Example II

Start with the method of Example I and add the following modificationsand additions to the noted steps of Example I:

To Step 1.1—1.0 M ⁸⁹YCl₃, weighing out non-radioactive (i.e., Y-89)YCl₃.6H₂O and transferring quantitatively to a volumetric flask; addingdeionized water to the volumetric flash; agitating to mix completely;and

Step 1.2—drawing up the 1.0 M ⁸⁹YCl₃ solution into a syringe and pushingthe solution through a filter and collecting the solution in a sterilecontainer; and

Step 3—radioactive (⁹⁰Y+⁸⁹Y) PO₄ synthesis procedure;

Step 3.1—adding 1.0 ml of H₂O to the microwave reaction vial with asterile magnetic stir bar and placing the reaction vessel on a stirplate and with continuous stirring;

Step 3.2—adding 2.67 ml of 0.15 M Na₂HPO₄; and

Step 3.3—adding 0.32 ml of ⁸⁹YCl₃ solution; and

Step 3.4—adding up to 0.05 ml of ⁹⁰Y in 0.05 M HCl from a source vial;and

Step. 3.5—recording the final pH and

Step 3.6—transferring the vial to a microwave reactor;

Step 3.7—setting the reaction temperature to 150° C. and reaction timeto one hour and starting the reactor;

Step 4—final steps

Step 4.1—adjusting the pH of the product solution with 1.0 N NaOH to pHrange of 1.5 to 8;

Step 4.3—removing supernatant leaving 1.0 ml in the vial for eachscheduled tumor treatment.

Example III

Start with the method of Example II and add the following modificationsand additions to the noted steps of Example II:

Step 1.1—1.0 M ⁸⁹YCl₃: weighing out non-radioactive (i.e., Y-89) YCl₃6H₂O for a single scheduled tumor treatment to the nearest 0.01 g)3.03±0.15 g and transferring quantitatively to a 10 ml volumetric flask;adding 10 ml deionized water to the 10 ml mark; agitating to mixcompletely; and

Step 1.2—drawing up ˜8-10 ml of 1.0 M ⁸⁹YCl₃ into a syringe and pushingthe solution through a filter and collecting the solution in a sterilecontainer; and

Step 1.3—preparing and filtering 0.15 M Na₂HPO₄ and 0.05 M HCl reagents;and

Step 4—final steps

Step 4.1—adjusting the pH of the product solution with 1.0 N NaOH to pHrange of 7 to 8; and

Step 4.2—removing supernatant leaving 1.0 ml in the vial for eachscheduled tumor treatment.

Example IV

An alternate method of preparing a radioactive yttrium phosphateparticle suspension comprises:

Using a hydrothermal process wherein a solution of yttrium salts fromthe group of yttrium chloride, yttrium nitrate, yttrium sulfate, andyttrium bromide is combined with a solution of sodium phosphate having astoichiometric excess of phosphate and a pH when combined in the rangeof 1.5 to 8; combining the solutions with continuous stirring andheating in a closed vessel to the range of 110° C. to 160° C. andholding for 1 to 20 hours to yield greater than 99.99% conversion ofsoluble yttrium to insoluble YPO₄ and to achieve a particle sizedistribution wherein the particles are equal to or less than 2 um; and

Creating the desired particle size distribution of YPO₄ particlessuspended in buffered saline at neutral pH suitable for direct injectioninto human or animal tissue.

Example V

Start with the method of Example IV and add the following modificationsand additions to the noted steps of Example IV:

The heating of the combined solutions is a rapid heating.

Example VI

Start with the method of Example V and add the following modificationsand additions to the noted steps of Example V:

the radioactive particle suspension employed by the method comprises atleast 90 percent of the total particle volume consisting of particles inthe range of 0.1 μm to 2 μm.

Example VII

Start with the method of Example VI and add the following modificationsand additions to the noted steps of Example VI:

employing a starting concentration of soluble yttrium in the combinedsolution that is in the range of 0.5 to 3.0 mole/liter and thestoichiometric excess of phosphate ranges from 10 to 100%.

Example VIII

Start with the method of Example VI and add the following modificationsand additions to the noted steps of Example VI:

employing a starting concentration of soluble yttrium in the combinedsolution that is 0.08 moles/liter and the stoichiometric excess ofphosphate is 25%.

Example IX

Start with the method of Example IV and add the following modificationsand additions to the noted steps of Example IV:

mixing and heating the particle suspension formed by preparing theparticle precursor solution to form the YPO₄ particles by controlledprecipitation followed by post-processing the particles to achieve asuspension of YPO₄ particles in phosphate buffered saline solution atneutral pH suitable for injection into human or animal tissue.

Example X

Start with the method of Example IX and add the following modificationsand additions to the noted steps of Example IX:

performing the post processing by rinsing the particles three times withsterile phosphate buffered saline (PBS) solution and removing or addingPBS to achieve the final desired volume.

Example XI

Start with the method of Example IX and add the following modificationsand additions to the noted steps of Example IX:

Performing the post processing by adjusting the pH of the final solutionwith sodium hydroxide then removing excess solution or adding sterilePBS to achieve the final desired volume.

Example XII

Start with the method of Example IV and add the following modificationsand additions to the noted steps of Example IV:

employing a particle suspension wherein the yttrium phosphate particlesare radioactive to serve as distributed sources of therapeutic radiationfor treating cancerous tumors and other diseases; and

making the particles radioactive by adding a small mass of solubleradioactive isotope to the particle precursor solution of Example IVthat becomes homogeneously incorporated into the insoluble yttrium

Example XIII

Start with the method of Example IV and add the following modificationsand additions to the noted steps of Example IV:

Using an yttrium phosphate particle suspension of Example IV wherein theparticle concentration is in the range of 40 mg/ml to 125 mg/ml tofacilitate imaging by x-ray computed tomography after being combined ina ratio of 1 to 4 by volume with biocompatible hydrogel or othersuitable liquid carrier solution and injection into human or animaltissue; and

using a solution of sodium phosphate having a stoichiometric excess ofphosphate and a pH in the range of 7 to 8.

1. The method of preparation of yttrium phosphate particles comprising:preparing reagents weighing out a non-radioactive (i.e., Y-89) yttriumsalt from the group of yttrium chloride, yttrium nitrate, yttriumsulfate, and yttrium bromide and transferring quantitatively to avolumetric flask; adding deionized water, agitating to mix completely;and drawing up the ⁸⁹YCl₃ solution from the volumetric flask into asyringe and pushing the solution through a filter and collecting thesolution in a sterile container; and preparing and filtering 0.15 MNa₂HPO₄ and 0.05 M HCl reagents; storing the reagents at roomtemperature; and preparing a radioactive ⁹⁰YCl₃ solution by adding to asource vial containing ⁹⁰YCl₃ a sufficient volume of 0.05 M HCl toachieve recovery of the desired quantity of radioactive material fromthe source vial; and performing a radioactive (⁹⁰Y+⁸⁹Y) PA₄ synthesisprocedure comprising: adding H₂O to a microwave reaction vial with asterile magnetic stir bar and placing the reaction vessel on a stirplate; and with continuous stirring and adding 0.15 M Na2HPO₄ and adding⁹⁰Y₃ solution; and adding ⁹⁰Y in 0.05 M HCl from a source vial; andrecording the final pH and transferring the vial to a microwave reactor;and setting the reaction temperature to a temperature in the range of110° C. to 160° C. and reaction time to between one hour and 20 hoursand starting the reactor, and taking final steps of placing themicrowave vial with the particles in a centrifuge, subjecting theparticles to centrifugation; and removing the supernatant liquid andreplacing with sterile phosphate buffered saline, and repeating thefinal steps two additional times; and then removing excess supernatantliquid from the vial; and labeling the vial with identity, lot number,and date of manufacture.
 2. The method of preparation of yttriumphosphate particles of claim 1 and further comprising: Step 1.1—1.0 M⁸⁹YCl₃, weighing out non-radioactive (i.e., Y-89) YCl₃.6H₂O andtransferring quantitatively to a volumetric flask; adding deionizedwater to the volumetric flash; agitating to mix completely; and Step1.2—drawing up the 1.0 M ⁸⁹YCl₃ solution into a syringe and pushing thesolution through a filter and collecting the solution in a sterilecontainer; and Step 3—radioactive (⁹⁰Y+⁸⁹Y) PO₄ synthesis procedure;Step 3.1—adding 1.0 ml of H₂O to the microwave reaction vial with asterile magnetic stir bar and placing the reaction vessel on a stirplate and with continuous stirring; Step 3.2—adding 2.67 ml of 0.15 MNa₂HPO₄; and Step 3.3—adding 0.32 ml of ⁸⁹YCl₃ solution; and Step3.4—adding up to 0.05 ml of ⁹⁰Y in 0.05 M HCl from a source vial; andStep 3.5—recording the final pH and Step 3.6—transferring the vial to amicrowave reactor; Step 3.7—setting the reaction temperature to 150° C.and reaction time to one hour and starting the reactor; Step 4—finalsteps Step 4.1—adjusting the pH of the product solution with 1.0 N NaOHto pH range of 1.5 to 8; Step 4.3—removing supernatant leaving 1.0 [sic]ml in the vial for each scheduled tumor treatment.
 3. The method ofpreparation of a volume of yttrium phosphate particles of claim 2further comprising: Step 1.1—1.0 M ⁸⁹YCl₃; weighing out non-radioactive(i.e., Y-89) YCl₃.6H₂O for a single scheduled tumor treatment to thenearest 0.01 g) 3.03±0.15 g and transferring quantitatively to a 10 mlvolumetric flask; adding 10 ml deionized water to the 10 ml mark;agitating to mix completely; and Step 1.2—drawing up ˜8-10 ml of 1.0 M⁸⁹YCl₃ into a syringe and pushing the solution through a filter andcollecting the solution in a sterile container; and Step 1.3—preparingand filtering 0.15 M Na₂HPO₄ and 0.05 M HCl reagents; and Step 4—finalsteps Step 4.1—adjusting the pH of the product solution with 1.0 N NaOHto pH range of 7 to 8; and Step 4.2—removing supernatant leaving 1.0 mlin the vial for each scheduled tumor treatment.
 4. A method of preparinga radioactive yttrium phosphate particle suspension comprising: using ahydrothermal process wherein a solution of yttrium salts from the groupof yttrium chloride, yttrium nitrate, yttrium sulfate, and yttriumbromide is combined with a solution of sodium phosphate having astoichiometric excess of phosphate and a pH when combined in the rangeof 1.5 to 8, combining the solutions with continuous stirring andheating in a closed vessel to the range of 110° C. to 160° C. and heldfor 1 to 20 hours to yield greater than 99.99% conversion of solubleyttrium to insoluble YPO₄ and to achieve a particle size distributionwherein the particles are equal to or less than 2 μm and Creating thedesired particle size distribution of YPO₄ particles suspended inbuffered saline at neutral pH suitable for direct injection into humanor animal tissue.
 5. The method of claim 4 wherein the heating in aclosed vessel is rapid heating of the combined solutions.
 6. The methodof claim 5 wherein the radioactive particle suspension created iscomprised of at least 90 percent of the total particle volume comprisingparticles in the range of 0.1 μm to 2 μm.
 7. The method of claim 6wherein the starting concentration of soluble yttrium in the combinedsolution is in the range of 0.5 to 3.0 mole/liter and the stoichiometricexcess of phosphate ranges from 10 to 100%.
 8. The method of claim 6wherein the starting concentration of soluble yttrium in the combinedsolution is 0.08 moles/liter and the stoichiometric excess of phosphateis 25%.
 9. The method of claim 4 wherein the particle suspension isformed by preparing the particle precursor solution of claim 4, mixingand heating said precursor solution to form the YPO₄ particles bycontrolled precipitation followed by post-processing the particles toachieve a suspension of YPO₄ particles in phosphate buffered salinesolution at neutral pH suitable for injection into human or animaltissue.
 10. The method of claim 9 wherein the post processing of theparticle suspension consists of rinsing the particles about 3 times withsterile phosphate buffered saline (PBS) solution and removing or addingPBS to achieve the final desired volume.
 11. The method of claim 9wherein the post processing of the particle suspension consists ofadjusting the pH of the final solution with sodium hydroxide then eitherremoving excess solution or adding sterile PBS to achieve the finaldesired volume.
 12. The method of claim 4 wherein the yttrium phosphateparticles of the particle suspension are radioactive to serve asdistributed sources of therapeutic radiation for treating canceroustumors and other diseases; and making the particles radioactive byadding a small mass of soluble radioactive isotope to the particleprecursor solution and homogeneously incorporating the isotopes into theinsoluble yttrium phosphate particle matrix.
 13. The method of claim 4wherein the particle concentration of the yttrium phosphate particlesuspension is in the range of 40 mg/ml to 125 mg/ml to facilitateimaging by x-ray computed tomography after being combined in a ratio ofabout 1 to 4 by volume with biocompatible hydrogel or other suitableliquid carrier solution and injection into human or animal tissue andwhere the solution of sodium phosphate having a stoichiometric excess ofphosphate and a pH in the range of 7 to 8.